Mycophenolate Mofetil Versus Azathioprine in Treatment Naive Autoimmune Hepatitis

NCT02900443 | Unknown Phase 4 DMC

• 1 other identifier: NL57115.058.16
• Study Type: interventional
• Target: 70
• Locations: 2 countries
• Sites: 14

Brief Summary

Rationale: Current standard therapy of autoimmune hepatitis consists of a combination of prednisolone and azathioprine. However, a significant proportion of patients does not respond to, or is intolerant for, azathioprine. Mycophenolate mofetil (MMF) has surpassed azathioprine as therapy to prevent organ transplant rejection and is sometimes used as an alternative option for autoimmune hepatitis. Several case series and one prospective study have documented the efficacy and safety of mycophenolate mofetil as induction therapy for autoimmune hepatitis. Robust evidence from a formal randomized clinical trial is lacking. Objective: To assess the efficacy and safety of mycophenolate mofetil as induction therapy in patients with treatment naive autoimmune hepatitis. Study design: Multicenter, randomised, open-label intervention study Study population: Patients with newly diagnosed autoimmune hepatitis who are in need of induction therapy according to current guidelines. Intervention: The intervention group will receive oral mycophenolate mofetil for 24 weeks. The control group will be treated with azathioprine for 24 weeks. Both groups will be treated with steroid induction which will closely follow the schedule from the recent Clinical Practice Guidelines by the European Association for Study of the Liver (EASL). Main study parameters/endpoints: The primary outcome is the proportion of patients in biochemical remission, defined as normalization of serum alanine transaminase (ALT) and immunoglobulin G (IgG) levels after 24 weeks of treatment, per treatment group. Secondary endpoints include safety and tolerability of mycophenolate mofetil, time to remission, changes in Model For End-Stage Liver Disease (MELD) -score (and its components bilirubin, INR, creatinine), albumin, pseudocholinesterase and N-terminal procollagen-III-peptide, ELF (Enhanced Liver Fibrosis) -score and aspects of quality of life.

Conditions

Autoimmune Hepatitis

Outcome Measures

Primary Outcomes (1)

• Biochemical remission

  The percentage of patients in biochemical remission, defined as normalization of serum ALT and IgG levels after 24 weeks of treatment, per treatment group.

  24 weeks

Secondary Outcomes (18)

• Time to biochemical remission

  24 weeks

• Biochemical remission at any time

  Up to 24 weeks

• Complete biochemical response, defined as normalization of AST, ALT and IgG at 6 months after initiation of treatment

  Up to 24 weeks

• Insufficient response, defined as lack of complete biochemical response determined at 6 months

  Up to 24 weeks

• Non-response at 4 weeks: defined as <50% decrease of serum transaminases within 4 weeks after initiation of treatment

  Up to 4 weeks

Study Arms (2)

Mycophenolate mofetil

EXPERIMENTAL

The intervention group will receive oral mycophenolate mofetil for 24 weeks. Both groups will be treated with steroid induction which will closely follow the schedule from the recent EASL Clinical Practice Guidelines.

Drug: Mycophenolate mofetil

Azathioprine

ACTIVE COMPARATOR

. The control group will be treated with azathioprine (standard of care) for 24 weeks. Both groups will be treated with steroid induction which will closely follow the schedule from the recent EASL Clinical Practice Guidelines.

Drug: Azathioprine

Interventions

Mycophenolate mofetil DRUG

Mycophenolate mofetil

Azathioprine DRUG

Azathioprine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Probable or definite diagnosis of autoimmune hepatitis according to the International Autoimmune Hepatitis Study Group criteria
• First presentation of AIH requiring treatment according to the current EASL guidelines
• Age ≥ 18 years
• Must provide informed consent and agree to comply with the trial protocol

You may not qualify if:

• Overlap syndrome with Primary Sclerosing Cholangitis (PSC) or Primary Biliary Cholangitis (PBC) (Paris criteria, strong positive Anti-Mitochondrial Antibodies (AMA), past liver biopsy or cholangiographic findings compatible with PBC or PSC).
• Presentation with acute liver failure, defined as presence of hepatic encephalopathy and coagulopathy (INR \> 1.5)
• Current treatment with prednisone/prednisolone and/or immunosuppressive medication for an indication other than autoimmune hepatitis
• Current systemic infection
• Other clinically significant medical conditions that could interfere with the trial
• If female of childbearing potential: known pregnancy, or unwilling to practice anticontraceptive measures.
• History of noncompliance with medical regimens, or patients who are considered to be potentially unreliable or unable to participate
• Mental instability or incompetence, such that the validity of informed consent or compliance with the trial is uncertain

Sponsors & Collaborators

• Radboud University Medical Center: lead
• Leiden University Medical Center: collaborator

Study Sites (14)

University Hospital Antwerpen

Antwerp, Belgium

Location

Zuyderland

Heerlen, Limburg, 6419 PC, Netherlands

Location

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, Netherlands

Location

Vrije Universiteit Medisch Centrum

Amsterdam, 1081 HV, Netherlands

Location

Amsterdam UMC, location AMC

Amsterdam, Netherlands

Location

Rijnstate Ziekenhuis

Arnhem, Netherlands

Location

Medisch Spectrum Twente

Enschede, Netherlands

Location

University Medical Center Groningen

Groningen, Netherlands

Location

Leiden University Medical Centre

Leiden, 2333ZA, Netherlands

Location

Maastricht UMC+

Maastricht, Netherlands

Location

Sint Antonius Hospital

Nieuwegein, 3430 EM, Netherlands

Location

Radboud University Medical Centre

Nijmegen, 6525GA, Netherlands

Location

Erasmus MC

Rotterdam, Netherlands

Location

Bernhoven

Uden, Netherlands

Location

Related Publications (1)

• Snijders RJALM, Stoelinga AEC, Gevers TJG, Pape S, Biewenga M, Tushuizen ME, Verdonk RC, de Jonge HJM, Vrolijk JM, Bakker SF, Vanwolleghem T, de Boer YS, Baven Pronk MAMC, Beuers U, van der Meer AJ, Gerven NMFV, Sijtsma MGM, van Eijck BC, van IJzendoorn MC, van Herwaarden M, van den Brand FF, Korkmaz KS, van den Berg AP, Guichelaar MMJ, Levens AD, van Hoek B, Drenth JPH; Dutch Autoimmune Hepatitis Working Group. An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitis. J Hepatol. 2024 Apr;80(4):576-585. doi: 10.1016/j.jhep.2023.11.032. Epub 2023 Dec 14.

  PMID: 38101756 DERIVED

MeSH Terms

Conditions

Hepatitis, Autoimmune

Interventions

Mycophenolic Acid; Azathioprine

Condition Hierarchy (Ancestors)

Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Thionucleosides; Sulfur Compounds; Mercaptopurine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Bart van Hoek, MD, PhD

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

• Joost PH Drenth, MD, PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 17, 2016
• First Posted: September 14, 2016
• Study Start: January 1, 2017
• Primary Completion: June 1, 2023
• Study Completion: June 1, 2023
• Last Updated: June 22, 2023

Record last verified: 2021-10

Locations

NL (13); BE (1)